Urea derivatives

ABSTRACT

A compound, or pharmaceutically acceptable salt thereof, having the formula: ##STR1## wherein X is O or S; wherein n=1 or 0; wherein R is C 3  -C 12  alkyl or aralkyl, branched or unbranched, aryl or haloaryl, or C 3  -C 22  alkenyl, branched or unbranched; wherein R 1  is OCH 3 , and wherein R 2  is OH. These urea derivatives have analgesic and anti-irritant activity when administered to humans and lower animals.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. application,Ser. No. 278,970, filed June 30, 1981 now abandoned.

TECHNICAL FIELD

This invention provides certain novel urea derivatives having analgesicand anti-irritant activity.

In general, analgesics fall into two broad categories. The simpleanalgesics, such as aspirin, are most effective against pain ofintegumental origin, headache, and muscle aches; the narcotics are moreuseful for deep or visceral pain. Narcotic analgesics such as morphinealso produce more profound effects than simple analgesics, and arepotentially addicting, with the development of tolerance and physicaldependence. The narcotic analgesics appear to work through interactionwith the endorphine/enkephalin system of the CNS; many of the simple,non-narcotic analgesics appear to work by inhibition of prostaglandinsynthetase. The effect of narcotics is to elevate the pain thresholdabove the normal level; the non-narcotic analgesics act to raise anabnormally low pain threshold to the normal level. The narcoticanalgesics are antagonized by N-allyl compounds such as naloxone; thenon-narcotic analgesics are not.

In the field of anti-irritancy, dermal and tissue irritation can becaused by common irritants such as acids and alkalis, keratolytics andproteolytics, depilatories, plant oils, and the like. In many instances,it is observed that compounds which effectively block the action of oneclass of irritants are totally or substantially ineffective with otherclasses of irritants. The problem in the art has been compounded by theinadequacy, or unavailability in some cases, of appropriate animalmodels of dermal irritation. For example, most laboratory animals areinsensitive to poison ivy. As a consequence, the search has longcontinued, in a purely empirical way, for anti-irritantcompositions--not always successfully.

The present invention relates to the discovery that certain novel ureaderivatives are analgesics and anti-irritants. In their analgesicaction, these compounds appear to be largely unrelated to the two knownclasses of analgesics. In certain tests, these compounds produce a levelof analgesia comparable to morphine, yet do not appear to involve theendorphin-enkephalin system, and thus should not be reversed by narcoticantagonists, such as naloxone. It is believed that these compounds willeffectively prevent the development of cutaneous hyperalgesia. At highdoses, it is believed that these compounds will also exert analgesicactivity in classical models of deep pain, elevating the pain thresholdabove the normal value.

In their anti-irritant activity, these compounds are active againstseveral irritants, including croton oil, and particularly depilatories(thioglycolates). They appear to act, not as protectants or barriers,but, rather, directly to block or eliminate responses to the irritantchemical. In addition, the urea derivatives of this invention offer thebenefit of reduced discomfort on application. By contrast, compoundssuch as capsaicin, which possess potent anti-irritant activity, cancause irritation and reddening of the skin.

BACKGROUND ART

J. A. Kiernan, Quart. J. of Exp. Physiol., (1977) 62, 151-161, statesthat capsaicin, N-(3-methoxy-4-hydroxybenzyl)-8-methyl-6-nonenamide, isknown to confer resistance to certain chemical irritants.

Jancso, et al., Br. J. Pharmac, Chemother. (1967), 31, 138-151, statesthat by repeated administration of capsaicin, ocular and/or cutaneouspain receptors can be desensitized to chemical, but not other, stimuli.

Arvier, et al., Br. J. Pharm. (1977), 59, 61-68, indicate that capsaicinreduces or blocks the edema formation associated with certain types ofinflammation.

DISCLOSURE OF THE INVENTION

The present invention provides compounds of the following formula:##STR2## wherein X is O or S; wherein N=1 or 0; wherein R is C₃ -C₁₂(preferably C₆ -C₁₂) alkyl or aralkyl, branched or unbranched, aryl orhaloaryl, or C₃ -C₂₂ (preferably C₆ -C₂₂) alkenyl, branched orunbranched; wherein R₁ is H, OH or OCH₃ and R₂ is H or OH (at least oneof R₁ and R₂ being OH or OCH₃) when n=1, and wherein R₁ is OCH₃ or OHand R₂ is OH when n=0; and pharmaceutically acceptable salts thereof.These compounds or salts thereof are hereafter generally referred to asurea derivatives. The most preferred urea derivatives are those where Xis S, where n=1, where R₁ is OCH₃ and where R₂ is OH (theN-(3-methoxy-4-hydroxybenzyl) thiourea, and especially those where R isn-octyl, phenyl or 1,1,3,3-tetramethylbutyl. These compounds can be madeby synthesis from readily available starting materials, using standardsynthetic techniques, as described hereinafter. In the practice of thisinvention, these urea derivatives can be administered either topicallyor systemically.

A. Definitions

By "safe and effective amount" is meant an amount of the urea derivativesufficient to provide analgesic or anti-irritant activity so as toalleviate or prevent the pain or irritation being treated at areasonable benefit/risk ratio attendant with any medical treatment. Theamount of the urea derivative used will vary with the particularcondition being treated, the severity of the condition, the duration ofthe treatment, the specific formulation employed and the concentrationof the urea derivative therein, and like factors.

By "systemic administration" is meant introducing the urea derivative orcomposition containing same into the tissues of the body, other than bytopical application. Systemic administration thus includes, withoutlimitation, oral, intrathecal, epidural, intramuscular, intravenous,intraperitoneal, and subcutaneous administration.

By "pharmaceutically acceptable" salts is meant those salts which aresafe for topical or systemic administration. These include the sodium,potassium, calcium, magnesium, and ammonium salts.

By "topical application" herein is meant directly laying on or spreadingthe urea derivative, or composition containing same, on epidermal orepithelial tissue (including outer skin and oral, gingival, nasal, etc.tissue).

By the term "comprise" as used herein is meant that various other inertingredients, compatible drugs and medicaments, and steps can be employedin the compositions and processes of this invention as long as thecritical urea derivatives are present in the compositions and are usedin the manner disclosed. The term "comprising" thus encompasses andincludes the more restrictive terms "consisting essentially of" and"consisting" which characterize the use of the essential ureaderivatives in the compositions and methods disclosed herein.

By "compatible" herein is meant that the components of the compositionare capable of being co-mingled without interacting in a manner whichwould substantially decrease the efficacy of the total compositionsunder ordinary use situations.

All percentages herein are by weight of the composition unless otherwisespecified.

B. Synthesis of the Urea Derivatives of the Present Invention

The urea derivatives of this invention can readily be prepared bysynthesis along the lines of the following schematic and illustraiveexamples for the N-(3-methoxy-4-hydroxybenzyl and3-methoxy-4-hydroxyphenyl) ureas and thioureas. ##STR3##

EXAMPLE I

N-(3-methoxy-4-hydroxybenzyl)-N'-octylurea was prepared by the followingmethod.

1. 3-methoxy-4-(2-ethoxy-1-oxapropyl)-benzonitrile

2 ml of trifluoroacetic acid was added slowly to a chilled solution of20 g of 3-methoxy-4-hydroxybenzonitrile, 50.7 ml of ethyl vinyl etherand 50 ml tetrahydrofuran (THF). The mixture was stirred at roomtemperature overnight. 7.5 ml of triethylamine was added to the mixtureand stirring was continued for several minutes until the solvent wasevaporated. The residue was partitioned between 400 ml of diethyl etherand 100 ml 1N NaOH. The diethyl ether layer was washed successively with100 ml H₂ O and 100 ml brine, dried over MgSO₄ and evaporated to yield31.2 gm of 3-methoxy-4-(2-ethoxy-1-oxapropyl)benzonitrile.

2. 2-methoxy-4-aminomethyl-(2-ethoxy-1-oxapropyl)benzene

A solution of 5.0 g 3-methoxy-4-(2-ethoxy-1-oxopropyl)benzonitrile in 25ml anhydrous THF was added dropwise to 119.5 ml 1 M lithium aluminumhydride in THF. The mixture was heated at reflux for four hrs, cooled to0°, and the excess reagent quenched with 5 N NaOH. Precipitated aluminumsalts were removed by filtration and the THF was evaporated. The residuewas partitioned between 200 ml ether and 75 ml H₂ O. The ether layer waswashed with 75 ml of brine, dried over K₂ CO₃, filtered, and evaporatedto yield 3.63 g of2-methoxy-4-aminomethyl-(2-ethoxy-1-oxapropyl)benzene.

3. N-(3-methoxy-4-(2-ethoxy-1-oxapropyl)benzyl))-N'-octylurea

A solution of 2.92 g of octyl isocynate in 25 ml diethyl ether was addeddropwise to a stirred solution of 3.63 g of2-methoxy-4-aminomethyl-(2-ethoxy-1-oxapropyl)benzene in 25 ml diethylether cooled in an ice bath over a 30 minute period. The reactionmixture was allowed to stir four hours at room temperature. The solventwas evaporated to yield 6.66 g of the crude urea which was purified byvolumn chromatography on silica gel with 60% ethyl acetate-hexane,yielding 5.2 g of the urea.

4. N-(3-methoxy-4-hydroxybenzyl)-N'-octylurea

30 ml 1 N HCl was added to an ice cold solution of the urea in 50 ml ofTHF and the mixture was stirred for 45 minutes. The THF was removed invacuo and the residue was partitioned between 100 ml CH₂ Cl₂ and 100 mlH₂ O. The organic phase was then washed with 50 ml H₂ O and 50 ml brine,dried over K₂ CO₃, filtered and evaporated. The crude product wasrecrystallized from CH₂ Cl₂ pentane which yielded 3.07 gm of whitecrystals, M.P. 90°-92° C. Analysis calculated for C₁₇ H₂₈ N₂ O₃ : C,66.20; H, 9.15; N, 9.08. Found: C, 66.27; H, 9.22; N, 8.98.

The thioureas can be prepared more directly, because the less reactiveisothiocyanates selectively attack the amino group, obviating the needto protect and then de-protect the 4-hydroxy group: ##STR4##

EXAMPLE II

N-(3-methoxy-4-hydroxybenzyl)-N'-octylthiorea was prepared by thefollowing method.

N-3-methoxy-4-hydroxybenzyl)-N'-octylthiourea

10.6 ml of 5 N NaOH was added to a suspension of 5.0 g3-methoxy-4-hydroxybenzylamine hydrochloride in 35 ml dimethylformamide(DMF). The resulting solution was cooled in an ice bath and 4.96 g ofoctyl isothiocyanate was added dropwise. The reaction mixture wasstirred for six hours at room temperature, poured into 500 ml of H₂ O,and then extracted with three successive 100 ml portions of diethylether. The combined ether extracts were returned to the separatoryfunnel and extracted with 75 ml 1N HCl, 75 ml saturated NaHCO₃, 75 ml H₂O and 75 ml brine. The organic phase was dried over MgSO₄, filtered andevaporated. The crude product was crystallized from methanol yielding4.58 gm of white solid M.P. 100°-101°. Analysis calculated for C₁₇ H₂₈N₂ O₂ S: C, 62.94; H, 8.70; N, 8.64; S, 9.88. Found: C63.05; H, 8.67; N,8.66; S, 10.03.

EXAMPLE III

N-(3-methoxy-4-hydroxybenzyl)-N'-dodecylthiourea was similarly prepared:##STR5##

Analysis calculated for C₂₁ H₃₅ N₂ O₂ S: C, 66.20; H, 9.53; N, 7.33.Found: C, 66.33; H, 9.54; N, 7.33.

By use of the appropriate isocyanate or isothiocyanate in one of theforegoing syntheses, any and all of the compounds of this invention canbe prepared.

C. Topical Compositions

The urea derivatives as previously described are useful when topicallyapplied to skin. Compositions containing these compounds are also usefulfor topical application to skin. The compositions comprise a safe andeffective amount, usually at least about 0.5%, preferably from about 1%to about 2%, of the urea derivative. The balance of the compositionfurther comprises a pharmaceutically acceptable carrier. Suitablecarriers for the urea derivatives preferably remain in place on the skinas a continuous film and resist being washed off easily by perspirationor by immersion in water. Generally, the carrier is organic in natureand capable of having dispersed or dissolved therein the ureaderivative. Lotions, creams, solutions, gels and solids are commonphysical forms of the compositions herein. A more detailed descriptionof such forms follows.

1. Lotions

The lotions can comprise an effective amount of the urea derivative;from 1% to 25%, preferably from 3% to 15%, of an emollient; the balancebeing water, a C₂ or C₃ alcohol, or a mixture of water and the alcohol.Several emollients are known. Examples of such emollients are asfollows:

1. Hydrocarbon oils and waxes. Examples are mineral oil, petrolatum,paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, andperhydrosqualene.

2. Silicone oils, such as dimethylpolysiloxanes,methylphenylpolysiloxanes, water-soluble and alcohol-solublesilicone-glycol copolymers.

3. Triglyceride fats and oils such as those derived from vegetable,animal and marine sources. Examples include castor oil, safflower oil,cotton seed oil, corn oil, olive oil, cod liver oil, almond oil, avocadooil, palm oil, sesame oil, and soybean oil.

4. Acetoglyceride esters, such as acetylated monoglycerides.

5. Ethoxylated glycerides, such as ethoxylated glyceryl monostearate.

6. Alkyl esters of fatty acids having 10 to 20 carbon atoms. Methyl,isopropyl, and butyl esters of fatty acids are useful herein. Examplesinclude hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropylpalmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decylstearate, isopropyl isostearate, diisopropyl adipate, diisohexyladipate, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate,myristyl lactate, and cetyl lactate.

7. Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examplesthereof include oleyl myristate, oleyl stearate, and oleyl oleate.

8. Fatty acids having 9 to 22 carbon atoms. Suitable examples includepelargonic, lauric, myristic, palmitic, stearic, isostearic,hydroxystearic, oleic, linoleic, ricinoleic, arachidic, behenic, anderucic acids.

9. Fatty alcohols having 10 to 22 carbon atoms. Lauryl, myristyl, cetyl,hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl,behenyl, erucyl, and 2-octyl dodecyl alcohols are examples ofsatisfactory fatty alcohols.

10. Fatty alcohol ethers. Ethoxylated fatty alcohols of 10 to 20 carbonsatoms include the lauryl, cetyl, stearyl, isostearyl, oleyl, andcholesterol alcohols having attached thereto from 1 to 50 ethylene oxidegroups or 1 to 50 propylene oxide groups, or a mixture thereof.

11. Ether-esters such as fatty acid esters of ethoxylated fattyalcohols.

12. Lanolin and derivatives. Lanolin, lanolin oil, lanolin wax, lanolinalcohols, lanolin fatty acids, isopropyl lanolate, ethoxylated lanolin,ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylatedlanolin alcohols, acetylated lanolin, acetylated lanolin alcohols,lanolin alcohols linoleate, lanolin alcohols ricinoleate, acetate oflanolin alcohols ricinoleate, acetate of ethoxylated alcohols-esters,hydrogenolysis of lanolin, ethoxylated hydrogenated lanolin, ethoxylatedsorbitol lanolin, and liquid and semisolid lanolin absorption bases areillustrative of emollients derived from lanolin.

13. Polyhydric alcohols and polyether derivatives. Propylene glycol,dipropylene glycol, polypropylene glycol (M.W. 2000-4000),polyoxyethylene polyoxypropylene glycols, polyoxypropylenepolyoxyethylene glycols, glycerol, ethoxylated glycerol, propoxylatedglycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol,polyethylene glycol (M.W. 200-6000), methoxy polyethylene glycols 350,550, 750, 2000, 5000, poly[ethylene oxide] homopolymers (M.W.100,000-5,000,000), polyalkylene glycols and derivatives, hexyleneglycol (2-methyl-2,4-pentanediol), 1,3-butylene glycol,1,2,6-hexanetriol, ethohexadiol USP (2-ethyl-1,3-hexanediol), C₁₅ -C₁₈vicinal glycol, and polyoxypropylene derivatives of trimethylolpropaneare examples thereof.

14. Polyhydric alcohol esters. Ethylene glycol mono- and di-fatty acidesters, diethylene glycol mono- and di-fatty acid esters, polyethyleneglycol (M.W. 200-6000) mono- and di-fatty acid esters, propylene glycolmono- and di-fatty acid esters, polypropylene glycol 2000 monooleate,polypropylene glycol 2000 monostearate, ethoxylated propylene glycolmonostearate, glyceryl mono- and di-fatty acid esters, polyglycerolpoly-fatty acid esters, ethoxylated glyceryl monostearate, 1,3-butyleneglycol monostearate, 1,3-butylene glycol distearate, polyoxyethylenepolyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylenesorbitan fatty acid esters are satisfactory polyhydric alcohol esters.

15. Wax esters such as beeswax, spermaceti, myristyl myristate, stearylstearate.

16. Beeswax derivatives, e.g. polyoxyethylene sorbitol beeswax. Theseare reaction products of beeswax with ethoxylated sorbitol of varyingethylene oxide content, forming a mixture of ether-esters.

17. Vegetable waxes including carnauba and candelilla waxes.

18. Phospholipids such as lecithin and derivatives.

19. Sterols. Cholesterol, cholesterol fatty acid esters are examplesthereof.

20. Amides such as fatty acid amides, ethoxylated fatty acid amides,solid fatty acid alkanolamides.

The lotions further comprise from 1% to 10%, preferably from 2% to 5%,of an emulsifier. The emulsifiers can be nonionic, anionic or cationic.Examples of satisfactory nonionic emulsifiers include fatty alcoholshaving 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbonatoms condensed with 2 to 20 moles of ethylene oxide or propylene oxide,alkyl phenols with 6 to 12 carbon atoms in the alkyl chain condensedwith 2 to 20 moles of ethylene oxide, mono- and di-fatty acid esters ofethylene glycol wherein the fatty acid moiety contains from 10 to 20carbon atoms, fatty acid monoglycerides wherein the fatty acid moietycontains from 10 to 20 carbon atoms, diethylene glycol, polyethyleneglycols of molecular weight 200 to 6000, propylene glycols of molecularweight 200 to 3000, glycerol, sorbitol, sorbitan, polyoxyethylenesorbitol, polyoxyethylene sorbitan, and hydrophilic wax esters. Suitableanionic emulsifiers include the fatty acid soaps, e.g. sodium, potassiumand triethanolamine soaps, wherein the fatty acid moiety contains from10 to 20 carbon atoms. Other suitable anionic emulsifiers include thealkali metal, ammonium or substituted ammonium alkyl sulfates, alkylarylsulfonates, and alkyl ethoxy ether sulfonates having 10 to 30 carbonatoms in the alkyl moiety. The alkyl ethoxy ether sulfonates containfrom 1 to 50 ethylene oxide units. Satisfactory cationic emulsifiers arethe quaternary ammonium, morpholinium and pyridinium compounds. Certainof the emollients described in preceding paragraphs also haveemulsifying properties. When a lotion is formulated containing such anemollient, an additional emulsifier is not needed, though it can beincluded in the composition.

The balance of the lotion is water or a C₂ or C₃ alcohol, or a mixtureof water and the alcohol. The lotions are formulated by simply admixingall of the components together. Preferably the urea derivative isdissolved in the mixture. Optional components such as common additivescan be included. One common additive is a thickening agent at a level offrom 1% to 10% of the composition. Examples of suitable thickeningagents include: cross-linked carboxypolymethylene polymers, ethylcellulose, polyethylene glycols, gum tragacanth, gum kharaya, xanthangums and bentonite.

2. Creams

Compositions of this invention also can be formulated in a cream form.The creams comprise an effective amount of the urea derivative; from 5%to 50%, preferably from 10% to 25%, of an emollient; the balance beingwater. The emollients above described can also be used in the creamcompositions. Optionally the cream form contains a suitable emulsifier,as previously described. When an emulsifier is included, it is in thecomposition at a level from 3% to 50%, preferably from 5% to 20%.

3. Solutions

The compositions of this invention can be also formulated in a solutionform. The solution form comprises an effective amount of the ureaderivative; the balance being a suitable organic solvent. Suitableorganic materials useful as the solvent or a part of a solvent systemare as follows: propylene glycol, polyethylene glycol (M.W. 200-600),polypropylene glycol (M.W. 425-2025), glycerine, sorbitol esters,1,2,6-hexanetriol, ethanol, isopropanol, diethyl tartrate, butanediol,and mixtures thereof. Such solvent systems can also contain water.

These compositions in the solution form can be applied to the skin asis, or else can be formulated into an aerosol and applied to the skin asa spray-on. The aerosol compositions further comprise from 25% to 80%,preferably from 30% to 50%, of a suitable propellant. Examples of suchpropellants are the chlorinated, fluorinated and chlorofluorinated lowermolecular weight hydrocarbons. Nitrous oxide, carbon dioxide, butane,and propane are also used as propellant gases. These propellants areused at a level sufficient to expel the contents of the container.

4. Gels

Compositions herein can be formulated into a gel form by simply admixinga suitable thickening agent to the previously described solutioncompositions. Examples of suitable thickening agents have beenpreviously described with respect to the lotions.

The gelled compositions comprise an effective amount of the ureaderivative; from 5% to 75%, preferably from 10% to 50%, of an organicsolvent as previously described; from 0.5% to 20%, preferably from 1% to10% of the thickening agent; the balance being water.

5. Solids

The compositions of this invention can also be formulated into a solidform. Such forms have use as a stick-type composition intended forapplication to the lips or other parts of the body. Such compositionscomprise an effective amount of the urea derivative and from 50% to 98%,preferably from 60% to 90%, of the previously described emollients. Thiscomposition can further comprise from 1% to 20%, preferably from 5% to15%, of a suitable thickening agent, and optionally emulsifiers andwater. Thickening agents previously described with respect to the gelledcompositions are suitable herein.

Additives commonly found in topical compositions such as preservatives,e.g., methyl and ethyl-paraben, dyes and perfume can be included in anyof the previously described compositions.

D. Pharmaceutical Compositions and Dosage Forms for SystemicAdministration

The urea derivatives of the present invention are also useful when usedsystemically, for example by parenteral administration. The dosage ofthe urea derivative which is both safe and effective to provideanalgesic or anti-irritant activity will vary with the particularcondition being treated, the severity of the condition, the duration oftreatment, the specific urea derivative employed and its usageconcentration, and like factors within the specific knowledge andexpertise of the patient or the attending physician and commensuratewith a reasonable benefit/risk ratio associated with the use of any drugcompound. The systemic dosages and dosage ranges given herein are basedon delivery of the urea derivative to a 70 kg human and can be adjustedto provide equivalent dosages for patients of different body weights.

For mammals, especially humans, individual doses of from 0.1 mg to over100 mg with total dosages of from 0.5 mg to 500 mg are acceptable.Individual doses of from 0.5 mg to 50 mg with total dosages of from 1 mgto 100 mg are preferred. Individual doses of from 5 mg to 25 mg withtotal dosages of from 10 mg to 50 mg are especially preferred. Whiledosages higher than the foregoing are effective, toxicity and sideeffects will present problems in some individuals.

The urea derivatives can be administered parenterally in combinationwith a pharmaceutically acceptable carrier such as corn oil, CremophorEL, or sterile, pyrogen-free water and a water-miscible solvent (e.g,ethyl alcohol) at a practical amount of the urea derivative per dose.Parenteral administration can be by subcutaneous, intradermal,intramuscular, intraarticular, or intravenous injection. The dosage bythese modes of administration is usually in the range of from about 10mg. to about 500 mg. per day.

As used herein the term "pharmaceutically acceptable carrier" denotes asolid or liquid filler, diluent, or encapsulating substance. Someexamples of substances which can serve as pharmaceutical carriers forthe urea derivatives include: sugars such as lactose, glucose andsucrose; starches such as corn starch and potato starch; cellulose andits derivatives, such as sodium carboxymethylcellulose, ethyl cellulose,cellulose acetate, powdered tragacanth; malt; gelatin; talc, stearicacid, magnesium stearate; calcium sulfate; vegetable oils, such aspeanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerin, sorbitol,mannitol, and polyethylene glycol; sugar; alginic acid; pyrogen-freewater; isotonic saline; phosphate buffer solutions; cocoa butter(suppository base), emulsifiers, such as the Tweens® as well as othernon-toxic compatible substances typically used on pharmaceuticalformulations. Wetting agents and lubricants such as sodium laurylsulfate, as well as coloring agents, and preservatives, can also bepresent.

The pharmaceutical carrier employed in conjunction with the ureaderivative is used at a concentration sufficient to provide a practicalsize to dosage relationship. Preferably, the pharmaceutical carriercomprises at least about 98% by weight of the total composition.

E. Methods for Providing Analgesia and Anti-irritancy

The present invention encompasses methods for providing analgesia oranti-irritancy in humans or lower animals in need thereof byadministering a safe and effective amount, usually from about 10 mg toabout 500 mg per patient per day, of the urea derivative, usually as acomposition with a pharmaceutically acceptable carrier. The ureaderivatives and compositions containing same can be administered bytopical application or systemic administration. The urea derivatives andcompositions containing same can be used to treat pain and to provide ananalgesic effect in various disorders at the deeper structures, muscles,tendons, bursa and joints associated with disease and trauma, and invarious other conditions in which compounds such as aspirin and morphinehave heretofore been used to alleviate pain and discomfort.

A "stairstep" dose pattern of sequentially increasing doses is usefulfor intraperitoneal administration in overcoming temporary side effectsand in administering larger doses of the urea derivatives of thisinvention. Thus, the initial dose should be selected to provide minimalside effects, and subsequent doses should be increased until the desiredlevel of activity is obtained while still minimizing side effects. Ingeneral, an initial dose of 2-10 mg/kg can be conveniently used,followed by doubling of each subsequent dose until the desired level isreached. The doses are preferably separated by a period of at least twohours.

F. Depilatory Compositions Having Reduced Dermal Irritation and Methodsfor Reducing or Preventing Irritation Caused by Depilatory Agents

The present invention also encompasses depilatory compositions havingreduced dermal irritation, which comprise: (a) a depilatory amount (e.g.at least about 2%) of a thioglycolate depilatory agent; and (b) the ureaderivative in an amount effective to reduce the dermal irritation causedby the thioglycolate depilatory agent. The depilatory compositions canbe formulated using the pharmaceutically acceptable carriers previouslydescribed for topical compositions.

The present invention further encompasses a method for preventing orreducing the dermal irritation caused by a thioglycolate depilatoryagent, which comprises the step of applying to at least a portion of adepilated area the urea derivative (or composition containing same) inan amount effective to prevent or reduce the irritation caused bytreatment of the depilated area with the thioglycolate depilatory agent.

By "thioglycolate depilatory agent" is meant thioglycolic acid, itsalkali metal, alkaline earth metal, and ammonium salt(s), or mixtures ofthe acid and its salts(s).

By "an amount effective to prevent or reduce irritation" is meant anamount of the urea derivative (or composition containing same) effectiveto reduce or prevent the irritation caused by treatment of the depilatedarea with the thioglycolate depilatory agent at a reasonablebenefit/risk ratio. The amount of the urea derivative used will varywith the severity of the irritation, the duration of the treatment, thespecific formulation employed, the concentration of the urea derivativetherein, and like factors.

By "depilated area" is meant that area which is, or is about to be,depilated by treatment with a thioglycolate depilatory agent.

By the term "applying" with regard to preventing or reducing depilatoryirritation is meant the direct laying on or spreading of the ureaderivative (including compositions containing same) on skin tissue whichis, or is about to be depilated. The urea derivative can be appliedbefore and/or after treatment of the depilated area with thethioglycolate depilatory agent to prevent or reduce irritation causedthereby. Application of the urea derivative to the depilated area aftertreatment with the depilatory agent is preferred, especially when lowerconcentrations of the urea derivative area used. The number ofapplications needed to provide effective irritation prevention orreduction can depend upon the concentration or the urea derivative used,and when the urea derivative is applied in relation to the treatmentwith the depilatory agent. Application of the urea derivative soon afterdepilation, e.g. within abut 6 to about 12 hours, provides effectiveirritation prevention or reduction, especially in conjunction withadditional applications on subsequent days. Multiple applications (2 ormore sequential, time spaced applications) soon after depilation areparticularly effective. The length of time during which the ureaderivativee is left on the depilated area can also determine itseffectiveness. An application duration of at least about 1 hour,preferably from about 1 to about 2 hours, should provide effectiveirritation prevention or reduction.

Specific Embodiments of Compositions ContainingN-(3-Methoxy-4-Hydroxybenzyl and phenyl) Ureas and Thioureas

The following examples illustrate compositions within the scope of thepresent invention, but are not limiting thereof.

    ______________________________________                                        Embodiment I                                                                  Lotion                                                                        Isopropyl myristate         8%                                                Corn oil                    5%                                                Propylene glycol            5%                                                Triethanolamine oleate      5%                                                Xanthan gum                 0.5%                                              N--(3-methoxy-4-hydroxybenzyl)-                                                                           0.5%                                              N'--hexylurea                                                                 Water                       Balance                                           Embodiment II                                                                 Cream                                                                         Isopropyl myristate         5%                                                Sorbitol                    5%                                                Propylene glycol            10%                                               Triethanolamine stearate    17%                                               N--(3-methoxy-4-hydroxybenzyl)-N'--dodecylthiourea                                                        1%                                                Water                       Balance                                           Embodiment III                                                                Gel                                                                           Oleyl alcohol               1%                                                Propylene glycol            20%                                               Triethanolamine             0.5%                                              Ethanol                     57%                                               Carbomer 940                0.5%                                              N--(3-methoxy-4-hydroxybenzyl)-N'--                                                                       0.5%                                              cis-12-docosenylurea                                                          Water                       Balance                                           Embodiment IV                                                                 Solution                                                                      Propylene glycol            10%                                               Polyethylene glycol 400     2%                                                Tween 80 ®              1%                                                Ethanol                     50%                                               N--(3-methoxy-4-hydroxyphenyl)-N'--                                                                       1%                                                hexenylthiourea                                                               Water                       Balance                                           Embodiment V                                                                  Ointment                                                                      Oleyl alcohol               30%                                               Cetyl alcohol               40%                                               Propylene glycol            28%                                               N--(3-methoxy-4-hydroxyphenyl)-N'--cis-12-                                                                2%                                                hexadecenylurea                                                               ______________________________________                                    

Effectiveness of N-(3-Methoxy-4-Hydroxybenzyl and phenyl) Ureas andThioureas in Producing Analgesia and in Reducing or PreventingDepilatory Irritation A. Analgesia 1. Mouse Hot Plate Tests

The Mouse Hot Plate (MHP) model system is designed to detect andevaluate agents which elevate the threshold for the perception of pain.Classically, this method has been utilized primarily to evaluatenarcotic type analgesic agents such as morphine. Unless administered intoxic quantities, nonsteroidal anti-inflammatory agents such as aspirinor acetaminophen exhibit little or no activity in this system.

Male CF-1 mice were used. Animals were divided into groups of 8 to 12and then tested on the "hot plate" to determine their predrug responsetime which was 4.9 seconds (average). Each animal was then treated witheither a test composition (0.5% to 2% of the particular urea or thioureain an isotonic saline solution containing ethyl alcohol and Tween 80) ora control composition (same as test composition but without the urea orthiourea). Treatment was by injection prior to test initiation.

2. Procedure

The mice were placed on a 55° C. heated surface and their responses wereobserved. The endpoint is either a rapid fanning or licking of a paw. Toprevent physical injury, the animals were not allowed to remain incontact with the heated surface for more than 60 seconds. The exposuretime required to elicit the endpoint response is a measure of the painthreshold. The difference in time required to elicit the endpointresponse before and after treatment provides a measure of analgesia. Theincrease in time required to elicit the endpoint response in treatedanimals versus control composition is a second measure.

3. Results

The results from the MHP testing of the N-(3-methoxy-4-hydroxybenzyl orphenyl) ureas or thioureas were as follows:

                  TABLE I                                                         ______________________________________                                                                           Post-Drug                                                          Dosage***  Response                                   Compound      Method**  (mg/kg)    (sec)                                      ______________________________________                                        Aspirin*      O         360        6.0                                        Acetaminophen*                                                                              O         450        5.3                                        Morphine Sulfate*                                                                           IP        13         13.1                                       Morphine Sulfate*                                                                           IP        25         17.4                                       Control       SC        --         5.0                                        N--(3-methoxyl-4-                                                             hydroxybenzyl)                                                                Octylurea     SC        0.68 mM/kg 6.5                                        Octylthiourea SC        0.68 mM/kg 14.7                                       Dodecylthiourea                                                                             SC        0.68 mM/kg 6.5                                        Phenylthiourea                                                                              SC        0.68 mM/kg 8.0                                        4-fluorophenylthiourea                                                                      SC        0.68 mM/kg 6.4                                        1,1,3,3-tetramethylbutyl-                                                                   IP        25         7.0                                        thiourea                                                                      N--(3-methoxy-4-                                                              hydroxyphenyl)                                                                Octylurea     SC        4,8,15,25,50                                                                             6.2                                        Octylurea     IP        4,8,15,25  11.5                                       Octylurea     SC        50         9.8****                                                  IP        50         52.8                                       Octylthiourea SC        0.68 mM/kg 9.5                                        ______________________________________                                         *Commercial Analgesics                                                        **O  oral; SC  subcutaneous; IP  intraperitoneal                              ***Multiple doses were 2 hours apart                                          ****IP dose was 24 hrs. after SC dose; 40% of animals dead               

The data in Table I shows that bothN-(3-methoxy-4-hydroxybenzyl)-N'-octylthiourea and -phenylthioruea, aswell as N-(3-methoxy-4-hydroxyphenyl)-N'-octylurea and octylthiourea,have significant analgesic activity relative to the control compositionand the commercial anagesics.

B. Preventing or Reducing Depilatory Irritation

Groups of 8 male Sprague-Dawley rats weighing 90-115 grams were used fortesting the effectiveness of the N-(3-methoxy-4-hydroxybenzyl or phenyl)urea and thioureas of the present invention in preventing or reducingdepilatory irritation. The animals were clipped and depilated withNair®, a commercially available thioglycolate depilatory. The testcompositions (2% of the urea or thiorea in an isotonic saline solutioncontaining 48% ethyl alcohol, 4% Tween 80) or a control composition(same as test composition but without the urea or thiourea) were appliedto one quadrant (Treated Area) of the depilated area once, 2 hours afterdepilation on first day; four times, 2 hours apart on second day; andthree times, 2 hours apart on third day for a total of eightapplications. The duration of each application was 2 hours. Theremaining three quadrants of the depilated area were left untreated(Untreated Area). Oral ingestion was prevented by the use of"Elizabethan" collars. On the fourth day, the animals were depilated asecond time and evaluated for irritation four hours later.

Irritation scores for each animal were determined by visual inspectionusing the following subjective evaluation scale:

    ______________________________________                                        Score   Description of Irritation                                             ______________________________________                                        0       No irritation                                                         0.5     No scab formation, faint white scale                                  1.0     Scab formation (pale orange/orange) over less                                 than 10% of area                                                      2.0     Mild to moderate intensity scab formation (pale                               orange) over 10-33% of area                                           3.0     Mild to moderate intensity scab formation (pale                               orange) over 33-75% of area                                           3.5     Moderate intensity scab formation (pale orange,                               occasional deep orange/red) over 75-90% of area                       4.0     Moderate to severe intensity scab formation                                   (deep orange, occasional pale orange) over                                    90-100% of area                                                       5.0     Severe intensity scab formation (deep                                         orange/red) over 100% of area                                         ______________________________________                                    

The irritation scores were totaled for each of the 8-animal groups, themaximum cumulative score being 40. A cumulative score of less than 8indicated a minimal level of irritation; a score of 8-24 indicated ahigher, but acceptable level of irritation; a score of above 24indicated an unacceptable level of irritation. The results from thistesting of the N-(3-methoxy-4-hydroxybenzyl or phenyl) ureas andthioureas were as follows:

                  TABLE II                                                        ______________________________________                                                         Cumulative Score                                                                            Untreated                                      Composition        Treated Area                                                                              Area                                           ______________________________________                                        Control            26.5        20                                             N--(3-methoxy-4-hydroxyphenyl)-                                               octyl thiourea     15          6                                              octyl urea         16          9                                              N--(3-methoxy-4-hydroxybenzyl)*                                               1,1,3,3-tetramethylbutylthiourea                                                                 1.3         13.3                                           phenylthiourea     15.3        30.0                                           ______________________________________                                         *extrapolated from group of 6 animals                                    

The data in Table II shows thatN-(3-methoxy-4-hydroxyphenyl)-N'-octylurea and octylthiourea, andN-(3-methoxy-4-hydroxybenzyl)-N'-1,1,3,3-tetramethylbutylthiourea, wereeffective in preventing or reducing depilatory irritation in both theTreated and Untreated Areas; theN-(3-methoxy-4-hydroxybenzyl)-N'-phenylthiourea was effective in theTreated Area.

What is claimed is:
 1. Compounds of formula: ##STR6## wherein n=1 or 0,wherein X is O or S when n=1, wherein X is S when n=0, wherein R is C₃-C₁₂ alkyl or aralkyl, branched or unbranched, haloaryl, or C₃ -C₂₂alkenyl, branched or unbranched, wherein R₁ is H, OH or OCH₃ and R₂ is Hor OH when n=1, at least one of R₁ and R₂ being OH, and wherein R₁ is OHor OCH₃ and R₂ is OH when n=0; and pharmaceutically acceptable saltstherof.
 2. The sodium, potassium, calcium, magesium, or ammonium salt ofthe compounds of claim
 1. 3. A compound or salt according to claim 1wherein R₁ is OCH₃ and wherein R₂ is OH.
 4. A compound or salt accordingto claim 3 wherein X is S.
 5. A compound or salt according to claim 4wherein n=1.
 6. A compound or salt according to claim 5 wherein R is C₆-C₁₂ alkyl or aralkyl, or C₆ -C₂₂ alkenyl.
 7. A compound or saltaccording to claim 6 wherein R is 1,1,3,3-tetramethylbutylphenyl orn-octyl.
 8. A pharmaceutical composition in unit dosage form havinganalgesic activity which comprises a safe and effective amount of acompound of formula: ##STR7## wherein X is O or S, wherein n=1 or 0,wherein R is C₃ -C₁₂ alkyl or aralkyl, branched or unbranched, haloaryl,or C₃ -C₂₂ alkenyl, branched or unbranched, wherein R₁ is H, OH or OCH₃and R₂ is H or OH when n=1, at least one of R₁ and R₂ being OH, andwherein R₁ is OH or OCH₃ and R₂ is OH when n=0, or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable carrier.
 9. Acomposition according to claim 8 wherein the pharmaceutically acceptablesalt is a sodium, potassium, calcium, magnesium, or ammonium salt.
 10. Acomposition according to claim 8 wherein R₁ is OCH₃ and wherein R₂ isOH.
 11. A composition according to claim 10 wherein X is S.
 12. Acomposition according to claim 11 wherein n=1.
 13. A compositionaccording to claim 12 wherein R is C₆ -C₁₂ alkyl or aralkyl, or C₆ -C₂₂alkenyl.
 14. A composition according to claim 13 wherein R is n-octyl.15. A method for providing analgesia in humans and lower animals in needthereof, whihc comprises the step of administering to the human or loweranimal a safe and effective amount of a compound of formula: ##STR8##wherein X is O or S, wherein R is C₃ -C₁₂ alkyl or aralkyl, branched orunbranched, aryl or haloaryl, or C₃ -C₂₂ alkenyl, branched orunbranched, wherein R₁ is H, OH or OCH₃ and R₂ is H or OH when n=1, atleast one of R₁ and R₂ being OH, and wherein R₁ is OH or OCH₃ and R₂ isOH when n=0; or a pharmaceutically acceptable salt thereof.
 16. A methodaccording to claim 15 in which the compound or salt is administeredtopically.
 17. A method according to claim 15 in which the compound orsalt is administered parenterally.
 18. A method according to claim 17 inwhich the compound or salt is administered intramuscularly.
 19. A methodaccording to claim 17 in which the compound or salt is administeredsubcutaneously.
 20. A method according to claim 15 in which the compoundor salt is administered in sequentially increasing doses.
 21. A methodaccording to claim 20 in which the doses are separated by a period of atleast 2 hours.
 22. A method according to claim 15 wherein R₁ is OCH₃ andwherein R₂ is OH.
 23. A method according to claim 22 wherein X is S. 24.A method according to claim 23 wherein n=1.
 25. A method according toclaim 24 wherein R is n-octyl.
 26. A depilatory composition havingreduced dermal irritation, which comprises:(a) a depilatory amount ofthioglycolate depilatory agent, and (b) a compound in an amounteffective to prevent or reduce the dermal irritation of thethioglycolate depilatory agent and having the formula: ##STR9## whereinX is O or S, wherein n=1 or 0, wherein R is C₃ -C₁₂ alkyl or aralkyl,branched or unbranched, haloaryl, or C₃ -C₂₂ alkenyl, branched orunbranched, wherein R₁ is H, OH or OCH₃ and R₂ H or OH when n=1, atleast one of R₁ and R₂ being OH or OCH₃, and wherein R₁ is OH or OCH₃and R₂ is OH when n=0; and pharmaceutically acceptable salts thereof.27. A composition according to claim 26 which further comprises apharmaceutically acceptable carrier.
 28. A method for preventing orreducing the dermal irritation caused by a thioglycolate depilatoryagent, which comprises the step of applying to at least a portion of adepilated area a compound in an amount effective to prevent or reduceirritation caused by treatment of the depilated area with athioglycolate depilatory agent, the compound having the formula:##STR10## wherein X is O or S, wherein n=1 or 0, wherein R is C₃ -C₁₂alkyl or aralkyl, branched or unbranched, haloaryl, or C₃ -C₂₂ alkenyl,branched or unbranched, wherein R₁ is H, OH, or OCH₃ and R₂ is H or OHwhen n=1, at least one of R₁ and R₂ being OH or OCH₃, and wherein R₁ isOH or OCH₃ and R₂ is OH when n=0; and pharmaceutically acceptable saltsthereof.
 29. A method according to claim 28 wherein X is S, wherein n=1,wherein R is 1,1,3,3-tetramethylbutyl, wherein R₁ is OCH₃ and wherein R₂is OH.